Studies with genetically well-defined mouse models of Inflammatory Bowel Diseases, i.e. experimental colitis, lead to a general notion that several perturbations of the finely tuned balance between the immune system and the vast antigenic load of the colon can result in disease. Aggressor CD4+ T helper1 cells accumulate in the lamina propria followed by initiation of destructive cascades in the intestinal mucosa. Bacterial antigens or mouse antigens encoded by genes induced by colonic bacteria are presented to these T cell subsets by professional Antigen Presenting Cells (APC), macrophages, dendritic cells and M cells. In healthy mice the aggressor Th1 cells are prevented from expanding and thus initiating the destructive cascades by Suppressor (TS) T cells. Our general hypothesis is that the pathogenesis of colitis is the result of aberrant regulation of the innate and adaptive immune systems. The first hypothesis of this application is that the SLAM family of adhesion molecules in macrophage/dendritic cell CD4+ T cell interactions determine the induction and effector functions of aggressor T cells in the periphery. The second hypothesis is that well defined monoclonal antigen specific TS cells act via a bystander mechanism in colitis. The third hypothesis is that TS cells are educated in the thymus and act in the periphery, but can also prevent thymic destruction by aggressor T cells. The genetically well-defined mutant mouse strains that will be used in the experiments designed to prove these three hypotheses in turn will provide further evidence for the general hypothesis. The experiments proposed in this application are grouped into the following specific aims: 1). To study the role of the SLAM family of adhesion molecules which govern the interactions between macrophages and colitis inducing aggressor T cells. 2). Further define CD4+CD25+ TS cells that suppress colitis in the periphery via bystander suppression. 3). Test the hypothesis that CD4+CD25+ TS cells that suppress colitis are educated in the thymus and can prevent thymic destruction.